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The urokinase/urokinase receptor system mediates the IgG immune complex-induced inflammation in lung

Item Type:Article
Title:The urokinase/urokinase receptor system mediates the IgG immune complex-induced inflammation in lung
Creators Name:Shushakova, N. and Eden, G. and Dangers, M. and Zwirner, J. and Menne, J. and Gueler, F. and Luft, F.C. and Haller, H. and Dumler, I.
Abstract:Immune complex (IC) deposition induces an acute inflammatory response with tissue injury. IC-induced inflammation is mediated by inflammatory cell infiltration, a process highly regulated by the cell surface-specific receptor (uPAR), a binding partner for the urokinase-type plasminogen activator (uPA). We assessed the role of the uPA/uPAR system in IC-induced inflammation using the pulmonary reverse passive Arthus reaction in mice lacking uPA and uPAR compared with their corresponding wild-type controls. Both uPA-deficient C57BL/6J (uPA -/-) and uPAR-deficient mice on a mixed C57BL/6J (75%) ×(25%) background (uPAR -/-) demonstrated a marked reduction of the inflammatory response due to decreased production of proinflammatory mediators TNF-{alpha} and Glu-Leu-Arg (ELR)-CXC chemokine MIP-2. In uPAR -/- animals, the redaction of inflammatory response was more pronounced because of decreased migratory capacity of polymorphonuclear leukocytes. We show that the uPA/uPAR system is activated in lung of wild-type mice, particularly in resident alveolar macrophages (AM), early in IC-induced alveolitis. This activation is necessary for an adequate C5a anaphylatoxin receptor signaling on AM that, in turn, modulates the functional balance of the activating/inhibitory IgG FcγRs responsible for proinlammatory mediator release. These data provide the first evidence that the uPA/uPAR plays an important immunoregulatory role in the initiation of the reverse passive Arthus reaction in the lung by setting the threshold for C5a anaphylatoxin receptor/FcγR activation on AM. The findings indicate an important link between the uPA/uPAR system and the two main components involved in the IC inflammation, namely, complement and FcγRs.
Keywords:Alveolar Macrophages, Anaphylatoxin C5a Receptor, Antigen-Antibody Complex, Cell Surface Receptors, IgG Receptors, Immune Complex Diseases, Immunoglobulin G, Inbred C57BL Mice, Inflammation, Knockout Mice, Lung Diseases, Ovalbumin, Urinary Plasminogen Activator, Animals, Mice
Source:Journal of Immunology
Publisher:American Association of Immunologists
Page Range:4060-4068
Date:15 September 2005
Official Publication:http://www.jimmunol.org/cgi/content/abstract/175/6/4060
PubMed:View item in PubMed

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